Pyritinol is perhaps the oldest nootropic drug which is still in use - it
has been continuously used and researched in Europe since it was patented by
Merck in 1961. Surprisingly for a drug whose patent expired in the late 1970’s.

Pyritinol has generated as much published research in the 1980’s and 1990’s as
was generated in the early years of Pyritinol studies. This seems to be due to
the wide range of uses, safety, and efficacy of Pyritinol. Most of the research
on Pyritinol has been published in British, French, German, Czech, and Swiss
journals. Thus the drug is virtually unknown in America, not to mention ignored
by the AMA and FDA.

Pyritinol has been used clinically in a wide range of disorders. A 1981 report
states: "Pyritinol... is widely used throughout Europe for the treatment of
organic psychosyndromes..., cerebral circulatory disorders..., alcoholism...,
dyslexic factors..., behavior and intellect disorders in children... and
post-cerebral infarction [stroke] states....

In patients suffering from cerebral trauma it has been reported to be of
therapeutic benefit in influencing the immediate post-operative recovery state
and as an aid in rehabilitation...." (1)

Pyritinol has also shown excellent benefit on the clinical course of victims of
traumatic coma (caused by head injury). Pyritinol has both reduced the normal
high death rate in such cases, and has rapidly returned coma patients to more or
less normal waking consciousness, even when the brain injuries were so severe
the patient ultimately died. (2) Pyritinol has also been used successfully to
treat rheumatoid arthritis patients. (3) Pioneer nootropic researcher
I.Hindmarch has also noted that "The clinical properties of Pyritinol have also
been demonstrated using experimentally induced hypoxia [low brain oxygen] where
a 68% [decrease] on psychometric assessments was reduced to 21% by 600 mg and to
12% by 1000 mg of the drug." (4)

Pyritinol is also known as pyrithioxine, and pyridoxine disulfide.
In the Pyritinol molecule, two pyridoxine sulfide molecules are linked together
by their two sulfur atoms.

One of the keys to understanding Pyritinol’s wide mode of action was first
revealed in 1989. Two Czech scientists performed sophisticated experiments on 6
nootropic drugs to determine their free radical-quenching power. Pyritinol
proved to be far superior to the acknowledged antioxidant nootropics,
centrophenoxine (Lucidril) and DMAE, while piracetam and oxiracetam showed no
antioxidant effect. Pavlik and Pilar state: "There is growing evidence that
free-radical interactions are implicated in the pathogenesis of many diseases
including radiation injury, atherosclerosis, arthritis, cancer and aging.... The
most dangerous [kind] of oxygen radicals is the hydroxyl radical that can attack
proteins, lipids, nucleic acids and, actually, almost any molecule of a living
cell. If the production of hydroxyl radical escapes the control mechanisms, then
… substantial damage to cell functions [and structure] may occur.... It was
found that Pyritinol exerted a pronounced scavenger action against hydroxyl
radicals which was confirmed by the electron spin resonance spectroscopic
technique in spin trapping experiments". (5) It is interesting to note that
brain proteins were protected from hydroxyl radical damage by Pyritinol in these
experiments. As will now be explained, the superior hydroxyl radical antioxidant
effect of Pyritinol is what provides much of the immune, arthritis, and
neuroprotective benefits of Pyritinol.

Three of the most common ‘free radicals’ that are continuously being produced in
human cells are superoxide radical, hydrogen peroxide, and hydroxyl radical.
Superoxide radicals are normally produced through white blood cell germ-killing
activities, energy metabolism, and in many disease states. "It is believed that
the activity of superoxide is at least partly.... responsible for aging and most
if not all degenerative diseases". (6A)

Fortunately the body has two different enzymes - copper-zinc SOD and manganese
SOD - to neutralize superoxide radicals. Unfortunately, SOD production drops
with age: "Lowered levels of SOD... have been found in elderly persons....
Decreases in all human tissues examined have found in humans, progressing from
ages 1 to 89". (6B) SOD converts neutralize superoxide radicals into oxygen and
hydrogen peroxide. Hydrogen peroxide is less cell-damaging than neutralize
superoxide radicals, but it is still injurious if it accumulates in cells.

Although hydrogen peroxide has some uses in the body (e.g. white blood cells
secrete it to kill germs), the body’s need to continuously rid itself of
hydrogen peroxide is shown by the fact that our cells possess two completely
different enzymes - catalase and glutathione peroxidase - to ensure
neutralization of hydrogen peroxide. Hydrogen peroxide uncontrolled can damage
cell membranes and structures, as well as promote inflammation.

The brain is particularly vulnerable to damage by hydrogen peroxide. (6C)
Unfortunately, under conditions all too common in our cells, neutralize
superoxide radicals and hydrogen peroxide "will react with each other in what is
known as the Haber-Weiss reaction. The product of this reaction is a free
radical even more damaging than superoxide known as the hydroxyl radical...."
(6D). And to make matters worse, human cells have no enzymatic defense against
hydroxyl radical. hydroxyl radical is normally quenched primarily by
cholesterol, Vitamin C or proanthocyanidins, (6E). (Thus, the elevated
cholesterol levels found in most modern humans may actually be a defensive
tactic used by the body to quench the excesses of hydroxyl radical induced by
our toxic modern diet, environment and lifestyles). hydroxyl radical’s are so
injurious to cells that when huge uncontrollable numbers of them are generated
in a person exposed to massive levels of X-ray or gamma radiation, the flesh may
literally melt from the bones within hours!

As Pavlik and Pilar note: "There are some clinical reports that may be viewed as
supporting the opinion that Pyritinol may also have a [hydroxyl] scavenger
effect in vivo. Camus [et al] (1978) and Berry (1986) used Pyritinol
successfully, instead of the … more toxic scavenger penacillamine, for the
treatment of some cases of rheumatoid arthritis. [So did Lemmel et al, reporting
in 1993. (3)] The protection of cartilage and synovial protein against
free-radical -induced degradation … may be an important factor in the treatment
of rheumatoid arthritis. The same line of reasoning may be applied to some cases
of stroke or brain trauma ..., where the generation of hydroxyl free-radicals …
is abundant … and where Pyritinol was successfully used for treatment ....
Finally, the potency of Pyritinol to protect proteins in brain against radical
induced polymerization, in conjunction with recent reports that Pyritinol
enhanced cholinergic transmission in brain ..., substantiates its use for the
treatment of cognitive disorders". (5)

Increased brain cell energy

Another key benefit of Pyritinol has been known since the 1960’s: its ability to
enhance or normalize glucose transport through the blood-brain barrier and to
increase brain cell energy production from glucose.(7) In a placebo-controlled,
double-blind study, Hoyer and colleagues examined 87 patients suffering from
various brain disorders. Careful measurements of cerebral blood flow, oxygen
uptake, glucose uptake, and cerebral metabolic rate were taken. Of the 45
patients receiving Pyritinol, 27 (60%) suffered from disturbed glucose
uptake/cerebral energy metabolism. "Cerebral uptake of glucose, … which … was
reduced to approximately 50% of the normal value, increased significantly during
Pyritinol treatment … and returned to normal.... The clinical disturbances
generally also improved to the same extent as did the disturbed glucose
metabolism". (7)

Enhanced Glucose Transport

Pyritinol’s ability to enhance glucose transport through the blood-brain barrier
when it is low is a highly significant benefit of Pyritinol. Although the brain
is usually less than 2% of total bodyweight, the brain must produce and use
about 20% - 500 calories per day - of the body’s total energy production. And
under normal, non-fasting conditions, the brain can only ‘burn’ glucose (sugar)
for fuel. Unlike virtually all other body cells, nerve cells cannot use fat as
an energy fuel. Brain cells also cannot store any significant amount of glucose
- they are completely dependent upon a continuous delivery of glucose from the
blood, through the blood-brain barrier. Thus, brain glucose uptake is a major
rate-limiting factor for crucial brain energy production. Low cerebral glucose
uptake necessarily translates into low brain carbohydrate energy metabolism.

And brain energy metabolism is so important to optimal, healthy brain function
that "... brain carbohydrate metabolism is impaired in a variety of dementias
[e.g. Alzheimer’s, stroke, metabolic, or drug toxicity dementias] and … the
degree of reduction in brain carbohydrate metabolism is correlated with the
severity of the dementias ...." (7) Pyritinol is good for optimal brain
carbohydrate metabolism , and what is good for brain carbohydrate metabolism is
good for the brain and the mind!

Effective Immune Enhancer

A surprising effect of Pyritinol was first reported in 1993: Pyritinol may be an
effective immune enhancer through its stimulation of neutrophil migration. (9)
Neutrophils are a major type of white blood cell (WBC) - they typically
constitute about 60% of the total number of white blood cells in the blood.
Wherever there is a wound, cut, sore, abrasion etc., neutrophils are attracted
to leave the bloodstream and travel to the site of injury/infection - the
process of chemotaxis. Once at the site of injury, neutrophils proceed to engulf
germs - especially bacteria - that may now be growing at the injury site.
Neutrophils then secrete a powerful mix of free radicals and oxidants, such as
hydrogen peroxide and hypochlorous acid, which destroy the germs before they can
seriously multiply and overwhelm the body. However, neutrophils sooner or later
die "in the line of duty" from their own germ-killing free radical barrage.

One neutrophil averages 5 to 20 germ kills before succumbing. The free radicals
neutrophils release also typically promote inflammation at the site of injury, a
process that all too easily gets out of control and proceeds to excess.
Excessive inflammation promotes excessive swelling, tenderness, redness, heat
and pain at the injury site. The pus that forms with cuts and wounds is in large
part made up of dead neutrophils.

In a study with rabbit neutrophils, Elferink and De Koster found that Pyritinol,
at levels likely to be achieved in tissue, through oral doses, strongly promoted
neutrophil chemotaxis (migration to injury site), but did not increase free
radical levels or inflammation. (9) Given the earlier discussion on Pyritinol’s
antioxidant effects, this differential effect of Pyritinol on neutrophil
activity (increases migration, but not free radicals or inflammation) becomes
comprehensible. When large numbers of neutrophils release huge amounts of
hydrogen peroxide and hydrogen peroxide, this generates huge quantities of
inflammatory, tissue-damaging hydroxyl radicals. Yet Pyritinol is a powerful
quencher of hydroxyl radicals. Thus Pyritinol is able to reduce hydroxyl
radical-induced inflammation and tissue damage - the unpleasant side effect that
usually accompanies successful germ-killing by neutrophils.

ImmuneDefense

Neutrophils comprise the body’s first line of white blood cell immune defense -
they are normally first to arrive at wound/injury sites. Yet our modern
sugar-rich diet has been shown in multiple studies to significantly impair
neutrophil activity.

When human volunteers were given various forms and levels of sugar in drinks,
the number of germs a neutrophil could kill before dying from its own free
radical release typically dropped 50 - 80%! The effect began within one hour of
sugar intake, peaked at two hours, and was still significant five hours after
sugar ingestion. (10) Thus a sugar-rich diet literally enhances neutrophil
self-destruction as neutrophils kill germs, yet Pyritinol enhances neutrophil
survival through reducing the hydroxyl radical excesses that normally lead to
neutrophil death.

Another key property of Pyritinol is its vigilance-enhancing effect. Pyritinol
increases nerve activity in the locus coeruleus. (11) "In humans, the number of
neurons in the locus coeruleus declines with advancing age. Degeneration appears
to advance slightly faster in males than females. The locus coeruleus is a brain
area that … is particularly susceptible to neuronal degeneration in Alzheimer’s
disease.... [There are many] studies indicating a role of this system in control
of attention and … learning and memory". (11)

EEG Power

"Pyritinol has also been shown to produce a vigilance response, both
behaviorally and electrophysiologically (EEG recordings) in animals and in
healthy human volunteers. More recently, using topographic brain mapping of EEG,
it has been shown that 600 mg Pyritinol resulted in an increase in total (EEG)
power and … other changes indicative of improved vigilance.... Specific studies
of the effects of Pyritinol on … memory using a battery of seven tests … showed
that repeated daily doses of Pyritinol 300mg improved memory performance [which
is in part a function of locus coeruleus - regulated vigilance] over a wide
range of measures in volunteers aged from 16 to 66 years". (4)

Who might benefit?

1. Pyritinol may be useful in various forms of dementia, organic brain syndrome,
head injury, stroke aftermath, coma, and cerebral circulatory disorders.
Vinpocetine, piracetam, oxiracetam, and phosphatidyl serine may be useful
synergists with Pyritinol.

2. Pyritinol may be useful as an anti-brain aging nootropic drug.

3. Pyritinol may be useful as an aid to increased focus and concentration,
memory, alertness and information processing in both young and old, normal or
mildly brain dysfunctional persons.

5. Pyritinol may be useful as part of a health-optimizing antioxidant program,
along with vitamins C and E, selenium, zinc and lipoic acid.

6. Pyritinol may be useful in the treatment of rheumatoid arthritis. In a large,
double blind yearlong trial comparing Pyritinol to a standard anti-rheumatoid
drug (Auranofin), the response rate was superior for Pyritinol (78% vs. 59%, at
one year). "Every individual efficacy parameter showed a numerical trend for
better results in the Pyritinol group...." (3)

Pyritinol Side-Effects

Most published studies on Pyritinol report few if any side effects, with skin
rashes and/or gastric upset occasionally noted. E.g. "In general, the
tolerability of the drug was good. Practically no problems occurred during the
trial.... None of the reported symptoms were rated as serious or persisted over
a long period of time". (14) "No undesirable side-effects were observed". (13)
"With the exception of cutaneous [skin] symptoms ... there were no significant
differences in the incidence of adverse reactions in the drug and placebo
group.... No significant changes were observed in [clinical laboratory]
parameters". (1)

The one major exception to Pyritinol’s low side-effect profile occurred in the
large-scale rheumatoid arthritis trial. The authors note that Pyritinol side
effects "were mostly nuisance events, which led to stopping therapy [in some
cases], but did not constitute a health risk for the patient and were fully and
rapidly reversible." (3) However, they also note a general trend in the
Pyritinol-arthritis literature of about 2% potentially serious adverse effects
involving blood, kidney or liver, which makes it important for regular
monitoring of liver enzymes, urine status and blood cell status when using
Pyritinol to treat rheumatoid arthritis. Therefore, Pyritinol should be used in
rheumatoid arthritis treatment only with the knowledge and supervision of a
physician.

Pyritinol Doses

A wide range of doses have been used in Pyritinol studies. These have ranged
from as low as 100 mg twice daily (12) to 200 mg three time’s daily (14) or 200
mg four times daily. (15) For anti-aging, cognition-enhancing or antioxidant
purposes, 100 mg Pyritinol two or three times daily is generally safe and
adequate. Higher doses (400 - 1000 mg daily) should probably be used only with
physician supervision, just to err on the safe side. Pyritinol may be taken
either on empty stomach or after food, as desired. Persons only prone to
insomnia should probably only take Pyritinol morning and early afternoon. There
may be a mutual enhancement of action between Pyritinol and other nootropic
drugs, allowing/requiring lower doses of some or all the drugs in order to avoid
an over-excitation effect.REFERENCES